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Comparison of antidepressant classes and the risk and time
course of suicide attempts in adults: propensity matched, retrospective
cohort study

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Comparison of antidepressant classes and the risk and time
course of suicide attempts in adults: propensity matched, retrospective
cohort study

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Please confirm that you accept the terms of use.

Abstract

Placebo-controlled clinical trials have led to concern over possible
increased risk of suicide-related events in some populations exposed to
antidepressants.

Aims

To evaluate the risk of suicide attempts by antidepressant drug class and
the presence or absence of depression.

Method

A retrospective propensity-matched new-user cohort study was used to
compare participants with incident depression classified by
antidepressant treatment with each other and with the general
population.

Results

Among the treated group, the suicide attempt rate peaked in the month
prior to diagnosis then decreased steadily over the next 6 months. Among
the pharmacologically untreated group, the highest rate was seen in the
second month after diagnosis. Cohorts with depression had significantly
higher suicide attempt risk than the general population, but the treated
group did not differ significantly from the untreated group.

Conclusions

Patients on antidepressants did not have significantly higher risk
compared with untreated patients. No significant differences were
observed for patients treated with individual serotonin–noradrenaline
reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors
(SSRIs) or by class (SSRI v. SNRI cohorts).

Footnotes

This study was funded by Eli Lilly and Company, Indianapolis, per a
regulatory study request by the European Medicines Agency (EMA).

Declaration of interest

R.J.V. has received research grants from Eli Lilly and Company. D.P.,
I.S. and L.B.M. were employees of Eli Lilly and Company at the time this
research was conducted.

Since the mid-twentieth century, the question of whether an association exists
between antidepressant use and suicide-related events has been the subject of
ongoing interest.1 Although the initial enquiries were about adult users of antidepressants,
the focus expanded early on to include paediatric users.2–4 Both the US Food and Drug Administration (FDA) and the European Union
European Medicines Agency (EMA) responded with warnings for all or some of these
agents, leading to changes in patterns of medical care and use of antidepressants.5–7 Currently, specific concerns centre on the possibility of increased risk of
suicide-related events with the newer-generation serotonin–noradrenaline reuptake
inhibitor (SNRI) antidepressants including venlafaxine and duloxetine,
particularly when used by children, adolescents or young adults.8 However, the generalisability of previous study results to current medical
practice is unclear, as many have been limited by brief trial duration,9–12 varying definitions of suicide-related events, lack of statistical power
for rare events such as suicide or suicide attempt13–15 and inadequate control for non-random allocation, among other issues.16 The lack of a community-based estimate of the risk of suicide-related
events among people diagnosed with depression, but not treated with
antidepressants, has also been an important gap in the literature, as has the lack
of an estimate for the baseline rate of such events in people in the community at
large (i.e. the general population). This information is critically important to
the debate. Without the inclusion of these comparison groups in an analysis, it is
not possible to determine the extent to which the risk of suicide-related events
is the result of the underlying disease process itself, for example depression, to
a possible increase in risk because of the antidepressant treatment in general, or
to a possible increase in risk for specific antidepressant drugs or drug classes.
The present study, initiated in response to a regulatory request by the EMA, seeks
to address these gaps. Specifically, we aim to contribute to the debate in three
major ways. First, by relying on data on real-world depression treatment across
the USA from 1997 to 2007 to allow a focus on the most commonly used classes of
antidepressants (SNRIs, selective serotonin reuptake inhibitors (SSRIs) and
tricyclic antidepressants (TCAs)), to establish risk estimates for patients
treated with the newest group of antidepressants (SNRIs) relative to the other
classes. Second, by creating two distinct populations, an incident depression
cohort (both pharmacologically treated and untreated) and a general population
cohort against whom suicide attempt risk is compared. Third, by using state of the
art epidemiological and statistical methods to account for non-random allocation
for treatment and consequent differences in the characteristics of individuals in
the different cohorts, using propensity-matched new-user cohorts and multivariate
adjustment for known, measured covariates.

Method

Data source

This study used data from the IMS (formerly PHARMetrics) LifeLink Database,
a commercially available claims database provided by IMS Health.17 The LifeLink database is among the largest patient-centric databases
of longitudinal, integrated medical and pharmacy claims data in the USA,
making it ideal for studies of rare outcomes associated with commonly
prescribed drug therapies. The integrated data obtained for this study
included paid claims from 85 managed care plans nationally – representing 55
million covered lives – from January 1997 to December 2007. Two different
data extracts were obtained by the authors. One extract included all records
for patients with any mental health diagnosis (ICD-9 code 296.xx – 300.xx or 311.xx)18 or an antidepressant prescription dispensed or one or more medically
coded suicide attempts; this resulted in approximately 6 million adult
patients and was used to create the pharmacologically treated and untreated
depression groups. The second extract was a 10% random sample of the entire
LifeLink database, irrespective of diagnosis or treatment; this resulted in
approximately 3.5 million adult patients and was used to create a
community-based general population sample for comparison. Data were
unidentified and anonymous, and the study protocol and data use agreement
were approved by the Colorado Multiple Institutional Review Board (COMIRB,
Aurora, Colorado, USA).

Study cohorts

Figure 1 presents a consort chart
depicting the creation of the study cohorts. First, a prevalent cohort of
participants with current depression was created by identifying patients in
the LifeLink mental health extract with a claim for depression (ICD-9 code
296.2x, 296.3x, 300.4x or 311.xx) between 1 August 2004 and 30 June 2007.
Patients were excluded if they were younger than 19 years of age (to match
FDA age-group specifications) or had less than 6 months of continuous
insurance enrolment prior to any depression claim; this selection resulted
in a cohort of 1 155 356 participants age 19 and older with at least one
depression claim during the study period. The first depression claim was
identified as the participant's index depression diagnosis.

From the prevalent depression cohort, an incident depression cohort was
created by excluding patients who had less than 12 months of continuous
insurance enrolment prior to an index depression diagnosis or had any of the
following during the 12 months prior to their index depression diagnosis:
any previous depression diagnosis codes, receipt of any antidepressant or
receipt of any psychotherapy services as a paid claim. The time period prior
to a depression diagnosis was also used to assess other known risk factors
for suicide attempts, such as prior attempts. The resulting incident
depression cohort represents participants with ‘new’ episodes of depression;
it should be noted that these episodes are not necessarily ‘first-ever’
episodes, as the time period used for defining incident episodes was 1 year,
and participants may have had episode(s) at some point in the more distant
past.

The incident depression cohort (n = 434 498) was divided
into five mutually exclusive treatment groups: those with a dispensed
prescription for one of four types of antidepressants (SNRI, SSRI, TCA or
multiple antidepressants, defined below) within 30 days of their index
depression diagnosis, and those who did not receive antidepressant therapy
at all during the study period (untreated depression group). Participants
who received an antidepressant other than an SNRI, SSRI or TCA, and
participants who received an antidepressant more than 30 days after their
index depression diagnosis were excluded (n = 76 147).

Measures

Treatment/no treatment groups defined by drug class

Treatment groups were defined on the basis of a dispensed prescription
for one of four drug classes within 30 days following the index
depression date. The no treatment group was defined as the absence of an
antidepressant prescription dispensed of a given type during the study
period. SNRIs included duloxetine and venlafaxine and were identified
using Medi-Span Electronic Drug File™ (Med-File) v.2 Generic Product
Identifier (GPI) code 5818. SSRIs included citalopram, escitalopram,
fluoxetine, fluvoxamine, paroxetine and sertraline and were identified
using GPI code 5816. TCAs were identified using GPI code 5820. The
multiple antidepressants group was defined as at least one dispensed
prescription in a drug class under study within the first 30 days after
diagnosis and at least one antidepressant prescription dispensed from
another drug class within the 6-month follow-up period. Non-SNRI, -SSRI
or -TCA antidepressants – namely bupropion, isocarboxazid, maprotiline,
mirtazapine, nefazodone, phenelzine, selegiline, tranylcypromine and
trazodone – were excluded.

Index date

For the four antidepressant treatment groups (SNRI, SSRI, TCA or multiple
antidepressants), the index date was defined as the date of the first
dispensing of the drug in the study period. For the untreated depression
group, the index date was defined as the date of their index depression
diagnosis. For the general population sample, the index date was defined
as the index date for their match from the matched SNRI group.

Suicide attempt

The primary study outcome was suicide attempt leading to a medical
encounter. Suicide attempts leading to medical encounters were identified
from all medical or facility claim records by a diagnosis code in the
following range (following Centers for Disease Control and Prevention
guidelines): ICD-9 codes E950-E95919 or ICD-10 codes X60-X84 or Y87.0.20 Suicide attempts were considered study outcomes if they occurred
at any time during the follow-up period, which started on the index date
and lasted for 6 months; or up until the participant had a 1-month gap in
continuous insurance enrolment; or had their first suicide attempt.
Completed suicides are not captured in the LifeLink database and were
thus not included as an outcome measure in this study.

Covariates

Demographic covariates included gender, region (East, Midwest, South and
West), Medicaid status at time of index depression diagnosis and age at
index depression diagnosis. Age groups were created based on the
following definitions for comparison with FDA suicidality risk
communications: young adult, age 19–24 years; adult, age 25–64 years; and
older adult, age 65 and older.

Other covariates included both specific and total numbers of mental
health comorbidities; specific chronic and acute non-mental health
comorbidities; indices of chronic comorbidity including the Chronic
Disease Indicator (CDI)21 score and the Charlson comorbidity score;22 prior medication use (drug-months of exposure to both psychotropic
medications and all prescription medications); use of health services;
history of suicide attempt; severity of the index depression diagnosis;
physician-level covariates; and a market-level covariate reflecting rates
of prescribing of each drug group by generalist v.
specialist prescribers during the month that antidepressant therapy was
initiated. Covariates were all assessed during the 6 months prior to the
index depression diagnosis and are detailed in Tables 1 and 2.

Table 1 Demographic and clinical characteristics of the matched incident
depression cohorts and the community-based general population
sample

Statistical analysis

To account for non-random treatment allocation, we used propensity score
matching. This is among the strongest forms of adjustment, balancing
measured covariates for the treatment and comparison groups before analysis.23 First, the propensity for receiving an SNRI (v.
SSRI, TCA, multiple antidepressants or no antidepressants) was estimated for
each participant in the incident depression cohort using a multivariate
unconditional logistic regression model. This model included SNRI treatment
(yes/no) as the dependent variable and specified baseline patient-,
physician- and market-level measures as covariates. The sets of patient-,
physician- and market-level variables were based on prior research and
published literature and were assessed for each participant during the 6
months prior to their index depression diagnosis.

Next, participants in the SNRI group were matched to participants from the
SSRI, TCA, multiple antidepressants and no antidepressant groups, in a
pairwise fashion, using the propensity scores calculated in the previous
step. Matching ratios (i.e. the number of participants in the SNRI group
matched to those in each comparison group) were 1:3 for each drug-group pair
with the exception of TCA, which was matched to the SNRI group with a ratio
of 1:1 because of the small sample of adults receiving TCAs as initial
therapy. Caliper width (i.e. the allowable amount of deviation in scores
among matches) was set at 0.001 for each match. For each pairwise match, if
there were more than three (or one for TCA) participants that matched on
propensity score within 0.001, the participants to be matched were chosen
randomly from those eligible. This step in the pairwise matching on
propensity score resulted in an incident cohort of 52 355 participants. In
the original SNRI group, 69 participants did not have a match in any of the
other drug groups and therefore the size of the matched SNRI group is
slightly smaller than the original SNRI group.

The final step in creating the analytic cohort was to match participants
from the matched SNRI group (n = 8403) – the primary group
of interest – to participants in the 10% general population random sample.
Participants were matched on age (plus or minus 1 year), gender and region,
with up to 10 participants from the general population sample being matched
to each participant in the matched SNRI group. If there were more than 10
eligible matches from the general population sample for any participant in
the matched SNRI group, 10 general population sample participants were
randomly chosen for the match. The resulting analytic cohort included a
total of 128 111 participants (52 355 from the incident depression cohort
and 75 756 from the general population sample).

Analyses included both the propensity-matched drug-group cohorts and the
SNRI–general population sample cohort matched on age, gender and region
(n = 128 111). Analyses were initially stratified by age
group (young adult, adult and older adult), then combined and reported in
aggregate when similar results were obtained across stratified groups. SAS
version 9.1 was used for all data creation and analyses. An alpha-level of
0.05 and 95% confidence intervals were used to indicate statistical
significance.

To identify periods of potentially increased risk of suicide attempt in
relation to initiation of antidepressant treatment or no treatment, rates of
suicide attempt were aggregated monthly, by antidepressant class, in
relation to the patients' index date. Rates are reported per 100 000
participants for each month during the 6 months prior to and 6 months
following index dates by treatment cohort. For patients in the four
treatment groups, monthly incidence rates are anchored by the initiation of
antidepressant treatment; for patients in the untreated depression group,
incidence rates are anchored by the index depression diagnosis; and for
patients in the general population sample, incidence rates are anchored by
their SNRI-matched-participant index date. To characterise risk of suicide
attempt following initiation of treatment, crude suicide attempt rates
during the follow-up period were calculated per 100 000 participants for
each treatment/no treatment group. Absolute (attributable) risk differences
were calculated by subtracting the rate for each depression group (treated
and untreated) from the rate for the general population sample.

To estimate a fully adjusted effect of treatment group (SNRI, SSRI, TCA or
multiple antidepressants, untreated depression, general population sample)
on risk of suicide attempt, multivariate Cox proportional hazards regression
models were used, with propensity score included as a covariate, for the
outcome days to first suicide attempt. Patients with multiple suicide
attempts were censored at the time of first attempt, regardless of how many
additional attempts they may have had. Patients with no suicide attempt
during the follow-up period were by default censored at the end of
follow-up. Demographic characteristics, comorbidities, drug-months of
exposure to prior prescriptions (psychotropic and total) and suicide attempt
history were included in the models as covariates. Models were run
separately by age group and the referent group was varied to estimate the
statistical effects compared with the general population sample, untreated
depression group or the SNRI group, respectively.

Results

Descriptive statistics on the matched, incident depression cohort (treated and
untreated) and the general population sample are presented in Tables 1 and 2 (online Tables DS1–6 provide descriptive statistics on the cohorts
both prior to, and after, propensity score matching to illustrate both the need
for and the effect of the propensity score matching process, based on the
demographic and clinical characteristics of the study groups). As seen in Table 1, the study cohorts are comparable
on factors associated with suicide risk after propensity matching. Mean age of
study participants varied only from 41 to 44 years. Roughly two-thirds of each
cohort were women, as would be expected in samples of adults with depression;
the proportion of women was similar in the general population sample because of
age and gender matching. Based on the exclusion criteria used to create the
cohorts, by definition, there was no prior depression in the depression groups
during the 12 months prior to the index episode; 2.6% of the general population
sample had a depression diagnosis during the 6 months prior to their index
date. The most common comorbidity (Table
2) seen prior to the index date was anxiety spectrum disorder (5–8%
in the depression groups, 2% in the general population sample). Prevalence of
prior suicide attempt was low (Table 1),
ranging from 0.18% to 0.62% in the depression groups and only 0.01% in the
general population sample. The index depression diagnosis indicated recurrent
illness for 8–14% of patients (Table
1).

Monthly aggregated suicide attempt rates in relation to index date are
presented for all ages in Fig. 2. For all
the treated depression groups (SNRI, SSRI, TCA and multiple antidepressants),
suicide attempt rates were highest in the month before diagnosis and treatment
initiation, and steadily decreased over the next 6 months. The highest rate for
the untreated depression group was seen in the second month following the
depression diagnosis. Although the low rate for the general population sample
was difficult to determine from the figure, it was higher 6 months prior to the
index date (5.3 per 100 000) and 3 months following the index date (4.2 per 100
000) and displayed much less of a clear pattern or trend over time, as would
have been expected.

Fig. 2 Crude rates of suicide attempt during the 6 months prior to and
following the index antidepressant prescription date, all age groups
aggregated.

Figure 3 displays suicide attempt rates
for the follow-up period by age group. Young adult and adult groups are shown;
there were no suicide attempts to display in the older adult age group.
Treatment cohort crude suicide attempt rates are presented as absolute
(attributable) risk differences from the general population sample
community-based cohort. The multiple antidepressants group had the highest
suicide attempt rate, with an absolute risk difference (ARD) of 2156 additional
attempts per 100 000 and 498 additional attempts per 100 000 in the young adult
and adult cohorts, respectively, compared with the general population sample.
In the adult age group (ages 25–64), the untreated depression group had
statistically significantly higher suicide attempt rates (ARD of 163 additional
attempts per 100 000) relative to the general population sample, an ARD that
was higher than those observed for the SNRI, SSRI or TCA treated groups (ARDs
of 113, 81 and 79 additional attempts per 100 000 respectively). In the young
adult (age 19–24) age group, no suicide attempts were observed for participants
in the untreated depression or TCA groups, resulting in ARDs of 82 attempts per
100 000 lower (less) than the general population sample, although the rarity of
events in these two specific groups makes the estimates less precise.

Fig. 3 Rate of suicide attempt and absolute risk difference (ARD) for
depression cohorts relative to the general population sample (GPS)
cohort, by age group.

No results are presented for the older adult age cohort because there
were no suicide attempts in that group. Whiskers show 95% confidence
intervals. SNRI, serotonin–noradrenaline reuptake inhibitor; SSRI,
selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressant.

Table 3 presents multivariate Cox
proportional hazard model results on time to suicide attempt across the study
groups, stratified by age group (again, without reporting older adults because
of no events). The association of treatment drug class on suicide risk was
estimated fully adjusting for propensity to receive an SNRI, comorbidities,
drug-months of exposure to prior prescriptions and suicide attempt history,
among other relevant variables (listed in Tables 1 and 2). Three
separate multivariate models were estimated for young adults and adults; each
model varied the reference group (SNRI, untreated depression or general
population sample) in order to more fully describe the relative associations
between different classes of drug treatments and suicide risk. The top panel
reports hazard ratios (HR) with the general population sample as the referent
group. The depression cohorts, both treated and untreated, had significantly
higher risk for suicide attempt compared with the general population, with a
greater magnitude for adults over age 24 than for young adults. Indeed,
comparison with the general population sample as a referent group shows the
statistically significant association of depression with suicide risk present
in the study cohorts.

Table 3 The effect of study cohort on suicide attempt risk, estimated using
multivariate Cox proportional hazard models of time to suicide
attempt, stratified by age group with varying referent groupsa

Hazard ratio (95% CI)

Group

Young adult, age 19–24
(n = 12 673)

Adult, age 25–64 (n =
113 710)

Referent group, general population
sample

Serotonin–noradrenaline reuptake
inhibitor

7.62 (1.99–29.20)

9.00 (3.60–22.50)

Selective serotonin reuptake
inhibitor

4.51 (1.50–13.59)

6.87 (3.10–15.20)

Tricyclic antidepressant

NE

5.10 (0.64–40.84)

Multiple antidepressants

20.92 (7.81–56.04)

23.87 (11.70–48.73)

Untreated depression

NE

10.65 (2.11–53.80)

Referent group, untreated depression
group

Serotonin–noradrenaline reuptake
inhibitor

NE

0.85 (0.17–4.19)

Selective serotonin reuptake
inhibitor

NE

0.65 (0.14–3.02)

Tricyclic antidepressant

NE

0.48 (0.04–5.65)

Multiple antidepressants

NE

2.24 (0.50–10.02)

General population sample

NE

0.09 (0.02–0.46)

Referent group, serotonin–noradrenaline
reuptake inhibitor

Selective serotonin reuptake
inhibitor

0.59 (0.19–1.90)

0.76 (0.36–1.63)

Tricyclic antidepressant

NE

0.57 (0.07–4.46)

Multiple antidepressants

2.75 (0.97–7.82)

2.65 (1.63–5.16)

Untreated depression

NE

1.18 (0.24–5.86)

General population sample

0.13 (0.03–0.50)

0.11 (0.04–0.28)

NE, not estimable.

a. Older adult cohort not reported because there were no suicide
attempts in that age group; model s also adjusted for
comorbidities, drug-months of prior medications filled and suicide
attempt history. Results in bold are significant.

The middle panel reports hazard ratios using the untreated depression group as
the referent group; antidepressant-treated groups were not significantly
different from the untreated depression group on the relative hazard of suicide
attempt. These data are consistent with the illness of depression as the major
driver of suicide attempts, with rates decreasing on a population basis after
antidepressant treatment is initiated. Nonetheless, population data do not
fully address the risk of suicidal behaviour that has been reported in
placebo-controlled randomised trials in some populations (i.e. adolescents). As
such, clinical monitoring for suicide risk in at-risk populations is still
prudent.

The bottom panel reports results with the SNRI group as referent group in order
to examine suicide attempt risk associated with specific classes/types of
antidepressants. There was no significant difference in suicide attempt risk
between groups treated with SNRIs and SSRIs. There were only two SNRIs included
in the analysis – duloxetine and venlafaxine – and they were examined as
individual agents as well as an SNRI class (individual agent results provided
in online Table DS7). When compared with patients treated with duloxetine
(Table DS7), patients treated with venlafaxine (HR = 1.01, 95% CI 0.6–1.8) or
SSRIs (HR = 0.89, 95% CI 0.5–1.5) showed no statistically different rate of
suicide attempt. The multiple antidepressants group had significantly increased
risk of suicide attempt compared with the duloxetine subgroup (HR = 3.11, 95%
CI 1.9–5.0).

Discussion

Main findings

This study presents the most complete set of comparative risk estimates
published to date regarding the risk of suicide attempt associated with
antidepressant treatment in adults during naturalistic treatment. In
addition to antidepressant drug class v. class comparisons,
we included a general population cohort that permitted estimation of the
association between the underlying illness (depression) and suicide attempt.
In the Cox proportional hazard models, the depression cohort, whether
treated or untreated, had significantly higher risk for suicide attempt
compared with the general population. The comparison with an untreated
depression group further supports the hypothesis that depressive illness
underlies the risk of suicide attempt observed among the
antidepressant-treated groups. In fact, in comparison with the untreated
depression group, patients taking antidepressants of any individual class
did not have a significantly higher risk of suicide attempt. Only users of
multiple antidepressant classes (either concurrently or consecutively) had
higher risk of suicide attempt.

It might have been hypothesised that patients in the depression cohort who
were treated would have had lower rates of suicide attempt than those
individuals who were not. In reality, however, the lack of pharmacological
treatment in the untreated depression group may have reflected a judgement
by the prescribing physician that the patient's depression was mild and/or
that the perceived risk of suicide or other adverse outcomes was low, and
that pharmacological treatment was therefore not required. Conversely, given
that TCAs are increasingly reserved for more severely ill patients, a higher
rate of suicide attempts might have been expected in this cohort, but we did
not see this. The relatively low rate of suicide attempts in this group may
reflect the fact that TCAs are highly toxic and at times lethal in overdose
relative to SNRIs and SSRIs,24 and as a consequence prescribers may avoid their use in patients
considered to be at a risk of suicide. The risk of suicide attempt in the
multiple antidepressants group was significantly higher than in other
groups, perhaps reflecting a harder to treat patient population or a
situation in which the use of multiple antidepressant classes might carry
additional unknown risks.

SNRIs

Considering the SNRIs, there are only two individual agents in this class.
They were examined both individually and combined, with no differences in
results, thus providing the first results for the latest SNRI on the market,
duloxetine. Contrary to some previous reports,8,25 our study did not suggest the existence of a significantly higher
suicide attempt risk among patients using SNRIs as a class compared with
those using SSRIs. It may be that the SNRIs are reserved by prescribers for
the treatment of patients with severe or chronic depression or whose
depression is treatment-resistant compared with those prescribed SSRIs, so
the SNRI-treated group may represent one at higher risk of suicide attempt.26 Some prior studies have not controlled for baseline differences (such
as prior suicide attempt history), so more suicide attempts would be
expected in patients receiving SNRIs v. SSRIs. The fact
that our study controlled for many baseline differences makes the study
important, and may at least partially explain the lack of any observed
differences in risk of suicide attempt between the SNRI and SSRI cohorts.
Likewise, no differences among individual SSRI subgroups were detected (in
comparison with either fluoxetine as a referent SSRI, or the TCA, multiple
antidepressants or the untreated depression groups; results not shown,
because of lack of observed differences between groups).

Strengths and limitations

The cohort creation and multivariate methods used in this study represent
the state of the art in accounting for non-random allocation to treatment
and the associated confounding that might be observed in a treatment-outcome relationship.27 We used the standard approach of creating an incident depression
cohort with the associated clean sweep period. We then were able to utilise
the large sample size in our database to create propensity-matched cohorts.
Finally, we used further multivariate adjustment using measures of known,
measurable risk factors in claims data for later suicide attempt (such as
history of suicide attempt, prior depression episode) to further account for
residual confounding. Our results are consistent with prior work showing an
elevation in risk of suicide attempt prior to initiation of antidepressant
therapy, and a gradual reduction in risk over time after initiation.13,28

Limitations to this study should be taken into account when interpreting the
findings. Data for the study were drawn from integrated health insurance
claims records, which are subject to underreporting of diagnosis because of
stigma or financial disincentives, to underreporting of antidepressant
prescriptions because of the use of samples and to underreporting of suicide
attempts that may not reach the level of seriousness to result in a medical
claim, but may nevertheless be real. These limitations may potentially bias
our estimates in a downward direction, leaving the results as a low estimate
of the statistical parameter. There is no reason, however, to expect that
any of the possible underreporting would bias any one study group or finding
in a particular direction, or bias across-group (relative risk) comparisons.
Second, our study does not capture completed suicides, aborted attempts or
suicidal thoughts or ideation. Thus, only one dimension of suicide-related
behaviour is addressed, and our findings do not generalise to other
dimensions of this complex phenomenon. Further, the use of propensity score
matching, as intended, ‘levelled the playing field’ by making the study drug
groups more comparable in terms of many demographic and clinical variables,
but there were still some residual imbalances between the groups (such as
rates of recurrent depression were higher in the untreated depression group
and multiple antidepressants group than the single antidepressant groups).
In addition, propensity score matching can only match on the basis of
identified, measured confounders and there may be other confounders that are
either unknown or unmeasured, that contribute to residual differences
between groups. Finally, we did not study child or adolescent populations,
having addressed them in prior work,28 so our findings are generalisable only to adult populations.

In summary, although focusing on the risk of suicide attempt among users of
SNRI antidepressants, this study adds risk estimates to the literature on
key, previously unmeasured cohorts: the general population, with depression
but pharmacologically untreated and the SSRI, SNRI and multiple
antidepressants groups. We also contribute new data in regard to the most
recent SNRI introduced to the market. Large, retrospective new-user cohorts
are the ideal study design for such work because of the need to detect not
only the rare outcome of suicide attempt, but also to create statistically
matched cohorts. These estimates are readily interpretable for such metrics
as number needed to harm and likelihood of help and harm because they were
derived from real-world effectiveness samples from a broad-based US managed
care population. Future work will follow up on this analysis with further
investigation into the complexity of describing drug regimens and measuring
suicide-related behaviours and events among users of multiple
antidepressants, and the study of multiple suicide attempts over time.